TRULICITY

Dulaglutide is a human GLP-1 receptor agonist. The molecule is a fusion protein that consists of 2 identical, disulfide-linked chains, each containing an N-terminal GLP-1 analog sequence covalently linked to the Fc portion of a modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker and is produced using mammalian cell (Chinese hamster ovary) culture. The GLP-1 analog portion of dulaglutide is 90% homologous to native human GLP-1 (7-37). Structural modifications were introduced in the GLP-1 part of the molecule responsible for interaction with the enzyme dipeptidyl-peptidase-IV (DPP-4). Additional modifications were made in an area with a potential T-cell epitope and in the areas of the IgG4 Fc part of the molecule responsible for binding the high-affinity Fc receptors and half-antibody formation. The overall molecular weight of dulaglutide is approximately 63 kilodaltons. TRULICITY (dulaglutide) injection is a clear, colorless, sterile, preservative-free solution for subcutaneous use. Each single-dose pen contains a 0.5 mL solution of 0.75 mg, 1.5 mg, 3 mg, or 4.5 mg of dulaglutide and the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg for 0.75 mg and 1.5 mg; 0.125 mg for 3 mg and 4.5 mg), and trisodium citrate dihydrate (1.37 mg), in water for injection.

TRULICITY ® is indicated: As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors. TRULICITY ® is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated ( 1 ): As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.

Adult Dosage ( 2.1 ) Recommended starting dosage is 0.75 mg injected subcutaneously once weekly. After 4 weeks, the dosage may be increased to 1.5 mg once weekly for additional glycemic control. If additional glycemic control is needed, increase dosage in 1.5 mg increments after at least 4 weeks on the current dosage. Maximum recommended dosage is 4.5 mg injected subcutaneously once weekly. Pediatric Dosage ( 2.2 ) Recommended starting dosage is 0.75 mg injected subcutaneously once weekly. If additional glycemic control is needed, increase dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage. Recommendations Regarding Missed Dose ( 2.3 ) If a dose is missed, administer the missed dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. Important Administration Instructions ( 2.4 ) Administer once weekly at any time of day with or without food. Inject subcutaneously in the abdomen, thigh, or upper arm. 2.1 Adult Dosage The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly. Follow the dosage escalation below to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6.1 )]. After 4 weeks, the dosage may be increased to 1.5 mg once weekly for additional glycemic control. If additional glycemic control is needed, increase the dosage in 1.5 mg increments after at least 4 weeks on the current dosage. The maximum recommended dosage is 4.5 mg injected subcutaneously once weekly. 2.2 Pediatric Dosage The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly. If additional glycemic control is needed, increase the dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage to reduce the risk of gastrointestinal adverse reactions [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6.1 )] . 2.3 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to administer the dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. The day of weekly administration can be changed, if necessary, as long as the last dose was administered 3 or more days before the new day of administration. 2.4 Important Administration Instructions Prior to initiation, train patients and caregivers on proper injection technique [see Instructions for Use] . Administer TRULICITY once weekly, any time of day, with or without food. Inject TRULICITY subcutaneously in the abdomen, thigh, or upper arm. Rotate injection sites with each dose. Inspect TRULICITY visually before use. It should appear clear and colorless. Do not use TRULICITY if particulate matter or coloration is seen. When using TRULICITY with insulin, administer as separate injections and never mix. It is acceptable to inject TRULICITY and insulin in the same body region, but the injections should not be adjacent to each other.

TRULICITY is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY [see Warnings and Precautions ( 5.4 )] . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 ). Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components ( 4 ).

The following serious reactions are described below or elsewhere in the prescribing information: Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.5 )] Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.6 )] Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy [see Warnings and Precautions ( 5.7 )] Acute Gallbladder Disease [see Warnings and Precautions ( 5.8 )] Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥5%) are nausea, diarrhea, vomiting, abdominal pain, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks [see Clinical Studies ( 14 )] . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise. Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4 21.1 Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain c 4.9 6.5 9.4 Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6 4.2 5.6 Gastrointestinal Adverse Reactions In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than placebo -treated patients (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%). Adult Dose Ranging Trial for TRULICITY 3 mg and 4.5 mg Doses Table 2 shows adverse reactions occurring ≥5% in any of the treatment groups through 36 weeks in a clinical trial with 1842 adult patients with type 2 diabetes mellitus treated with TRULICITY 1.5 mg, 3 mg, or 4.5 mg subcutaneously once weekly as an add-on to metformin [see Clinical Studies ( 14.3 )] . The adverse reaction profile is consistent with previous clinical trials in adults. Table 2: Adverse Reactions That Occurred in ≥5% of TRULICITY-treated Adult Patients with Type 2 Diabetes Mellitus in a Clinical Trial through 36 Weeks a a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction TRULICITY 1.5 mg (N=612) % TRULICITY 3 mg (N=616) % TRULICITY 4.5 mg (N=614) % Nausea 13.4 15.6 16.4 Diarrhea 7.0 11.4 10.7 Vomiting 5.6 8.3 9.3 Dyspepsia 2.8 5.0 2.6 Other Adverse Reactions in Adults Hypoglycemia Table 3 summarizes the incidence of hypoglycemia in the placebo-controlled clinical studies in adult patients with type 2 diabetes mellitus: episodes with a glucose level <54 mg/dL with or without symptoms, and severe hypoglycemia, defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Table 3: Incidence (%) of Hypoglycemia in Adult Patients with Type 2 Diabetes Mellitus in Placebo-Controlled Trials Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Add-on to Metformin (26 weeks) N=177 N=302 N=304 Hypoglycemia with a glucose level <54 mg/dL 0 0.3 0.7 Severe hypoglycemia 0 0 0 Add-on to Metformin + Pioglitazone (26 weeks) N=141 N=280 N=279 Hypoglycemia with a glucose level <54 mg/dL 1.4 2.1 0 Severe hypoglycemia 0 0 0 Add-on to Glimepiride (24 weeks) N=60 - N=239 Hypoglycemia with a glucose level <54 mg/dL 0 - 3.3 Severe hypoglycemia 0 - 0 In Combination with Insulin Glargine ± Metformin (28 weeks) N=150 - N=150 Hypoglycemia with a glucose level <54 mg/dL 9.3 - 14.7 Severe hypoglycemia 0 - 0.7 Add-on to SGLT2i ± Metformin (24 weeks) N=140 N=141 N=142 Hypoglycemia with a glucose level <54 mg/dL 0.7 0.7 0.7 Severe hypoglycemia 0 0.7 0 Hypoglycemia was more frequent when TRULICITY was used in combination with a sulfonylurea or insulin than when used with non-secretagogues. In a 78-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 20% and 21% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. In a 52-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Severe hypoglycemia occurred in 2.7% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Refer to Table 3 for the incidence of hypoglycemia in patients treated in combination with basal insulin glargine. In the clinical trial with adult patients on TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, as add-on to metformin, incidences of hypoglycemia (glucose level <54 mg/dL) through 36 weeks were 1.1%, 0.3%, and 1.1%, respectively, and incidences of severe hypoglycemia were 0.2%, 0%, and 0.2%, respectively. Cholelithiasis and Cholecystitis In a cardiovascular outcomes trial in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors with a median follow up of 5.4 years [see Clinical Studies 14.5 ] , cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively. Heart Rate Increase and Tachycardia-Related Adverse Reactions In adult patients, TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Hypersensitivity Systemic hypersensitivity adverse reactions, sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling), occurred in 0.5% of adult patients on TRULICITY in clinical studies. Injection-site Reactions In the placebo-controlled studies in adults, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients. PR Interval Prolongation and Adverse Reactions of First-Degree Atrioventricular (AV) Block A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated adult patients in contrast to a mean decrease of 0.9 milliseconds in placebo-treated patients. The adverse reaction of first-degree AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Acute Pancreatitis In a pooled analysis from the original registration studies, 12 (3.4 cases per 1,000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1,000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1,000 patient years). Based on an analysis of adjudicated events in a clinical trial evaluating Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly, pancreatitis occurred in 1 patient exposed to TRULICITY 1.5 mg (0.2%), in 2 patients exposed to TRULICITY 3 mg (0.3%), and 3 patients exposed to TRULICITY 4.5 mg (0.5%). Amylase and Lipase Increase Adult patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%. Adverse Reactions in the Clinical Trial of Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus TRULICITY was administered to 150 pediatric patients 10 years of age and older with type 2 diabetes mellitus for a mean duration of 41.3 weeks [ see Clinical Studies ( 14.6 ) ]. The mean age was 14.5 years and 71% of patients were female. Overall, 55% were White, 15% were Black or African American, 12% were Asian, 10% were American Indian or Alaska Native, 5% were other races, and 3% had unknown race. Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity. At baseline, the mean duration of type 2 diabetes mellitus was 2 years, mean HbA1c was 8.1%, mean weight was 90.5 kg and mean BMI was 34.1 kg/m 2 . The safety profile in pediatric patients treated with TRULICITY 0.75 mg and 1.5 mg subcutaneously once-weekly was consistent with that described above for adult patients with type 2 diabetes mellitus with the exception of injection site reactions. In pediatric patients, the incidence of injection site reactions was 3.9% (2 patients) in the TRULICITY 0.75 mg group, 3.8% (2 patients) in the TRULICITY 1.5 mg group, and 2.0% (1 patient) in the placebo group. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of TRULICITY. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death, ileus Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy, cholestasis, elevation of liver enzymes, hepatitis Hypersensitivity: anaphylactic reactions, angioedema Neurologic : dysgeusia, dysesthesia Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation Renal: acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis Skin and Subcutaneous Tissue: alopecia

Oral Medications: Delays gastric emptying and has the potential to reduce the rate of absorption of concomitantly administered oral medications ( 7.1 ). 7.1 Oral Medications TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY [see Dosage and Administration ( 2.1 )] . The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg. Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )].

16.2 Storage and Handling Store TRULICITY in the refrigerator at 36°F to 46°F (2°C to 8°C). If needed, each single-dose pen can be kept at room temperature, not to exceed 86°F (30°C) for a total of 14 days. Do not freeze TRULICITY. Do not use TRULICITY if it has been frozen. Protect TRULICITY from light. Storage of TRULICITY in the original carton is recommended until time of administration.